The expanding worldwide HIV epidemic requires the expeditious development of an effective vaccine. Efforts to develop such a vaccine have been hampered by a lack of understanding of the correlates of protective immunity. Virus-specific cytotoxic T lymphocytes play a major role as a host defence in a number of viral infections, and a vigorous HIV-1- specific CTL response has been detected in HIV infected persons. Nevertheless, a chronic persistent infection develops in the majority if not all persons exposed to HIV, and is associated with progressive CD4 depletion and immunodeficiency. A better understanding of the relationship between progressive infection and disease development is likely to provide important insights into pathogenesis and have important impacts on vaccine development. The ability to measure responses to autologous virus should greatly facilitate such studies. The unfortunate infection of three laboratory workers with the HIV-IIIB strain provides a unique opportunity to evaluate the immune response in a setting whore the precise sequence of the infecting inoculum is known. l propose to perform a detailed analysis of the CTL response in these individuals. Specifically, I propose to a) identify the epitopes in structural and non-structural proteins which are targeted by CTL, b) evaluate the effects of sequence variations on CTL recognition, c) use TCR sequence analysis to track specific clonal responses over time, to determine whether clonal exhaustion contributes to declining CTL activity with disease progression.